International Journal of Molecular Sciences Review Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models Akihiro Yachie Division of Medical Safety, Kanazawa University Hospital, Kanazawa 920-8641, Japan; [email protected]; Tel.: +81-76-265-2073 Abstract: Since Yachie et al. reported the first description of human heme oxygenase (HO)-1 defi- ciency more than 20 years ago, few additional human cases have been reported in the literature. A detailed analysis of the first human case of HO-1 deficiency revealed that HO-1 is involved in the protection of multiple tissues and organs from oxidative stress and excessive inflammatory reactions, through the release of multiple molecules with anti-oxidative stress and anti-inflammatory functions. HO-1 production is induced in vivo within selected cell types, including renal tubular epithelium, hepatic Kupffer cells, vascular endothelium, and monocytes/macrophages, suggesting that HO-1 plays critical roles in these cells. In vivo and in vitro studies have indicated that impaired HO-1 production results in progressive monocyte dysfunction, unregulated macrophage activation and endothelial cell dysfunction, leading to catastrophic systemic inflammatory response syndrome. Data from reported human cases of HO-1 deficiency and numerous studies using animal models suggest that HO-1 plays critical roles in various clinical settings involving excessive oxidative stress and inflammation. In this regard, therapy to induce HO-1 production by pharmacological intervention represents a promising novel strategy to control inflammatory diseases. Keywords: heme oxygenase; HO-1 deficiency; oxidative stress; inflammation Citation: Yachie, A. Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and 1. Background Animal Models. Int. J. Mol. Sci. 2021, 22, 1514. https://doi.org/ Heme is a major component of hemoglobin (Hb), and is a product of erythrocyte 10.3390/ijms22041514 destruction. Heme is constantly produced in vivo through the destruction of both senescent erythrocytes under physiological conditions, and abnormal erythrocytes under pathological Academic Editor: József Balla conditions. Heme is extremely toxic to cells, so constitutive mechanisms exist to cancel the Received: 17 January 2021 toxic effects of heme [1,2]. Serum haptoglobin (Hp) binds to free Hb efficiently [3,4] and Accepted: 28 January 2021 the resulting Hb-Hp complex is promptly taken up by phagocytes and hepatocytes, which Published: 3 February 2021 express a receptor for the complex that is currently known as CD163 [5–7]. Heme oxygenase (HO)-1 constitutes one of the three isozymes of HO, and catalyzes the degradation of heme Publisher’s Note: MDPI stays neutral into biliverdin, carbon monoxide (CO), and free iron, each of which somehow exert potent with regard to jurisdictional claims in anti-oxidative stress and anti-inflammatory functions [8,9]. For this reason, HO-1 exerts published maps and institutional affil- protective properties in a broad range of human diseases, including neurodegenerative iations. diseases, cardiovascular diseases, cancer, metabolic diseases, iron metabolism disorders and various inflammatory diseases [10] (Figure1). Among the heme degradation products, CO plays a central role and acts on cellular metabolisms to protect cells from oxidative stress and regulate the production of inflam- Copyright: © 2021 by the author. matory molecules [11–13]. CO directly controls the inflammatory state of a given tissue, Licensee MDPI, Basel, Switzerland. and at the same time regulates the microcirculation within target organs by acting as a This article is an open access article gaseous mediator [14,15]. Among the three isozymes, HO-1 is the only protein rapidly distributed under the terms and induced upon stimulation with various oxidative stresses [14,16]. Therefore, any defect in conditions of the Creative Commons the function of HO-1 would be expected to lead to uncontrollable inflammation in response Attribution (CC BY) license (https:// to certain exogenous insults, such as infection and hemolysis. creativecommons.org/licenses/by/ 4.0/). Int. J. Mol. Sci. 2021, 22, 1514. https://doi.org/10.3390/ijms22041514 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 17 After Yachie et al. reported the first human case of HO-1 deficiency [17,18], 5 cases with identical mutation were recognized in India [19–21]. Additional cases with nonsense mutations and a case with a missense mutation have recently been reported [22–24]. In Int. J. Mol. Sci. 2021,this22, 1514 short review, I describe the clinical characteristics and laboratory features of these 2 of 16 cases and propose denominators for this extremely rare genetic disease. Figure 1. HemeFigure oxygenase 1. Heme oxygenase (HO)-1 and (HO)-1 the hemeand the degradation heme degradation pathway. pathway. Free hemoglobin Free hemoglobin (Hb) quickly(Hb) binds with haptoglobinquickly (Hp) to binds form awith molecular haptoglobin complex (Hp) (Hb-Hp). to form a Hb-Hp molecular is rapidly complex incorporated (Hb-Hp). Hb-Hp through is therapidly scavenger receptor, now knownincorporated as CD163, expressed through onthe the scavenger cell surface receptor, of tissue now macrophages known as CD163, such expre as hepaticssed on Kupffer the cell cells. surface Heme derived from Hb is degradedof tissue macrophages by HO-1 into such free ironas hepatic (Fe++), Kupffer carbon monoxidecells. Heme (CO) derived and from biliverdin. Hb is Biliverdindegraded by is furtherHO-1 degraded ++ into bilirubininto by free biliverdin iron (Fe reductase.), carbon All monoxide these heme (CO) degradation and biliverdin. products Biliverdin are known is further to exert degraded potent into anti-inflammatory bili- and anti-oxidativerubin by stress biliverdin functions, reductase. which inAll turn these play heme significant degradation roles inproducts preventing are known various to chronic exert potent diseases. anti-inflammatory and anti-oxidative stress functions, which in turn play significant roles in pre- venting various chronicAfter diseases. Yachie et al. reported the first human case of HO-1 deficiency [17,18], 5 cases with identical mutation were recognized in India [19–21]. Additional cases with nonsense 2. Case Reportsmutations of Human and HO-1 a case Deficiency with a missense mutation have recently been reported [22–24]. In this Althoughshort numerous review, studies I describe have the been clinical published characteristics utilizing and animal laboratory models features and in of these cases vitro experimentsand with propose regard denominators to the role of for HO-1 this in extremely vivo, only rare a limited genetic number disease. of human cases have been reported to date. Although the number of such cases remains limited, clinical descriptions2. Case of Reports these human of Human cases HO-1 of HO-1 Deficiency deficiency highlight the critical roles played by this enzymeAlthough in protecting numerous cells studies and organs have been from published oxidative utilizingstress and animal inflamma- models and in vitro tion. experiments with regard to the role of HO-1 in vivo, only a limited number of human cases have been reported to date. Although the number of such cases remains limited, clinical 2.1. The First Casedescriptions of these human cases of HO-1 deficiency highlight the critical roles played by In 1999, Yachiethis enzyme et al. reported in protecting on a cells26-month-old and organs boy from who oxidative had been stress admitted and inflammation. with recurrent fever, generalized erythematous rash, and joint pain [17]. The combination of 2.1. The First Case fever, erythematous rash, and joint pain suggested that the patient suffered from a child- hood chronic inflammatoryIn 1999, Yachie illness etsuch al. reportedas systemic on juvenile a 26-month-old idiopathic boy arthritis who had (sJIA) been or admitted with chronic infantilerecurrent neurological fever, cutaneous generalized and erythematous articular syndrome rash, and (alternatively joint pain called [17]. Thene- combination onatal-onset multisystemof fever, erythematous inflammatory rash, disease). and joint The pain latter suggested condition that is now the patientknown sufferedas from a cryopyrin-associatedchildhood periodic chronic syndrome. inflammatory However, illness neither such as of systemic these conditions juvenile idiopathic could ex- arthritis (sJIA) plain the uniqueor chronicclinical infantilefeatures neurologicaland extraordinary cutaneous laboratory and articular findings syndrome seen in this (alternatively pa- called tient. The patientneonatal-onset had characteristic multisystem facial feat inflammatoryures such as disease).a flat nasal The bridge, latter frontal condition boss- is now known as cryopyrin-associated periodic syndrome. However, neither of these conditions could ing, and prominent edema of the eyelids. Although the liver was markedly enlarged, the explain the unique clinical features and extraordinary laboratory findings seen in this spleen was absent. Unlike most patients with asplenia, this patient did not have any form patient. The patient had characteristic facial features such as a flat nasal bridge, frontal bossing, and prominent edema of the eyelids. Although the liver was markedly enlarged, the spleen was absent. Unlike most patients with asplenia, this patient did not have any form of congenital heart disease. His brother and sister appeared healthy, but